As the landscape of therapeutic treatment advances, orally available small molecule inhibitors remain a prominent weapon in the fight against disease. Perhaps nowhere is this approach more important than in the treatment of malaria, whose parasites infected over 200 million people and killed approximately 655,000 people in 2010. W.H.O., 2012. Prevention of malaria caused by the Plasmodium parasites has centered on the use of bed netting (which suffers from poor compliance), Frey, et al., 2006, and attempts to develop a vaccine (which has recently seen a breakthrough, albeit marginal), see The RTS, S., 2011, but the large number of people who still become infected continues to keep small molecule therapeutic treatment of paramount importance.
The history of malaria therapy is long and dozens of small molecules have been the treatment of choice at some point. Schlitzer, 2007. Well known examples include quinine, chloroquine, and atovaquone (compounds 1-3, respectively, FIG. 1). Each of these molecules (and others) has fallen from prominence, due either to significant side effects or to the development of parasite resistance, or both. Schlitzer, 2007. These chemical entities have been largely replaced by treatments containing the natural product artemisinin.
Artemisinin (4a, FIG. 2) could be considered one of the most significant natural product small molecule discoveries over the past 40 years. The molecule was first isolated from its natural source, Artemisia annua, in 1972 by a team under the direction of Dr. Youyou Tu. Miller and Su, 2011. It contains a surprisingly stable endoperoxide linkage that is essential for the demonstrated activity in a variety of diseases, most notably malaria and, more recently, several types of cancers and cytomegalovirus. He, et al., 2011. Unfortunately the molecule has poor bioavailability and is rapidly cleared from the body. Kyle, et al., 1998. First generation derivatives that attempt to circumvent this issue include lipid-soluble artemether (4b) and water-soluble artesunate (4c), and these molecules are now part of the first line of antimalarial treatment known as artemisinin combination therapy (ACT). Example combinations are Coartem® (artemether 4b plus lumefantrine 5, FIG. 3), Artequin® (artesunate 4c plus mefloquine 6, FIG. 3) and the recently FDA-approved Pyramax® (artesunate 4c plus pyronaridine 7, FIG. 3). Both artemether and artesunate, however, still have significant metabolic liabilities and short half-lives, so most new candidate drug combinations pair an artemisinin-derived analog with a drug that has better physical properties and a longer duration of activity. Further structure-activity relationships (SAR) have been explored around this peroxide linkage and have ranged from functionalization of the natural product, Haynes, et al., 2006; Araujo, N. C. P., et al., 2009; Pacorel, B., et al., 2010; Chadwick, et al., 2010; and Begue and Bonnet-Delpon, 2007; to completely synthetic peroxide structures. Singh, et al., 2012.; Dong, et al., 2005; Charman, et al., 2011; and Slack, R. D. et al., 2012. The pursuit of highly efficacious artemisinin derivatives and novel drug combinations continues.